The Neurobiology of the Stress Resistant Brain

抗压大脑的神经生物学

• 批准号: 8098911
• 负责人: MONIKA FLESHNER
• 金额: $ 33.34万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098911
• 关键词: Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Autoreceptors; Behavior; Behavior Control; Behavioral; Brain; Clinical; Data; Development; Exercise; Genes; Goals; Housing; Human; Lead; Learned Helplessness; Medial; Mental Depression; Mental disorders; Neurobiology; Neurons; Perception; Physical activity; Prefrontal Cortex; Prevention; Proteins; Rat Strains; Rattus; Recruitment Activity; Resistance; Role; Running; Serotonin; Stress; System; Testing; Work; behavior test; biological adaptation to stress; density; desensitization; design; dorsal raphe nucleus; experience; fitness; improved; innovation; locus ceruleus structure; mRNA Expression; noradrenergic; novel strategies; prevent; protective effect; psychologic; public health relevance; relating to nervous system; resilience; stress related disorder; stress resilience; stressor

DESCRIPTION (provided by applicant): Identification of means to prevent stress-related psychiatric disorders such as depression & anxiety is of primary importance. One manipulation with established stress resilient effects is exercise. We have observed that rats allowed access to running wheels are protected against the depression- & anxiety-like consequences of uncontrollable stress, or learned helplessness (LH). Growing evidence indicates that LH behaviors are produced by hyperactivation & sensitization of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Hyperactivation of DRN 5-HT neurons during stress could lead to later sensitization of these neurons by desensitizing 5-HT1A inhibitory autoreceptors in the DRN. Results from our prior work & preliminary studies suggest that wheel running prevents LH by constraining the activity of DRN 5-HT neurons during stressor exposure & preventing the desensitization of 5-HT1A autoreceptors. Constraint over 5-HT neural activity could be an adaptive feature of the stress response that is dysregulated in stress-related psychiatric disorders but facilitated by prior voluntary exercise. Understanding how the experience of exercise is communicated to the DRN to result in stress resilience is a primary goal of this project that has clear clinical implications for the prevention of stress-related disorders. Exercise is a unique behavioral manipulation that will likely recruit neurocircuits that together result in unique adaptations in the brain. To facilitate identification of these neurocircuits, we propose an innovative approach of controllable / yoked uncontrollable wheel running. Although voluntary wheel running is associated with stress resilience, forced exercise often fails to produce stress protective effects despite considerable fitness benefits. These data suggest that activity or fitness per se is not sufficient to produce stress resilience. Instead, exercise plus the psychological variable of "perceived control" may be critical. This is an important distinction because it implies involvement of distinct neural substrates involved in the perception of control (such as the medial prefrontal cortex; mPFC), vs. those simply recruited by physical activity per se (such as the noradrenergic system), in the stress resilience produced by exercise. Indeed, we have observed that voluntary exercise recruits both of these systems; repeated activation of which could contribute to the increase in DRN 5- HT1A autoreceptors by inhibiting the activity of the 5-HT1A gene repressor Freud-1. The current project tests the hypotheses that 1) wheel running prevents LH by preventing DRN 5-HT1A autoreceptor desensitization &/or increasing mPFC-inhibition of the DRN during stress, 2) the effects of wheel running on behavior & 5-HT1A autoreceptors are dependent on exercise controllability, & 3) repeated activation of the mPFC &/or DRN 11- ADRs contribute to the increase in 5-HT1A autoreceptors & the protective effect of wheel running against LH. PUBLIC HEALTH RELEVANCE: The goal of the current proposal is to identify how the experience of exercise is communicated to the central serotonergic system to result in resilience against stress- induced anxiety, focusing specifically on central circuits converging on the 5-HT1A autoreceptor. The results of this work will improve our basic understanding of the effects of stressor exposure and exercise on serotonin systems, and could lead to novel approaches for the prevention or treatment of stress-related psychiatric disorders.

描述（由申请人提供）：确定预防与压力有关的精神疾病（如抑郁和焦虑）的方法至关重要。一种具有既定压力弹性效果的方法是锻炼。我们已经观察到，允许老鼠进入滚轮可以保护老鼠免受抑郁和焦虑的后果，如无法控制的压力，或习得性无助（LH）。越来越多的证据表明，LH行为是由中脑背核（DRN）中5-羟色胺（5-HT）神经元的过度激活和敏化产生的。应激时DRN 5-HT神经元的过度激活可能导致DRN中5-HT1A抑制性自受体的脱敏，从而导致这些神经元的后期敏化。我们之前的工作和初步研究的结果表明，车轮运行通过在应激源暴露时抑制DRN 5-HT神经元的活性和防止5-HT1A自受体的脱敏来预防LH。对5-HT神经活动的限制可能是应激反应的一种适应性特征，在应激相关精神疾病中是失调的，但事先的自愿运动促进了应激反应。了解运动的经验是如何传达给DRN，从而导致压力恢复能力是这个项目的主要目标，它对预防压力相关疾病具有明确的临床意义。运动是一种独特的行为操纵，它可能会调动神经回路，从而在大脑中产生独特的适应性。为了方便识别这些神经回路，我们提出了一种创新的可控/轭不可控车轮运行方法。尽管自愿跑轮与压力恢复能力有关，但尽管有相当大的健身益处，强迫运动往往不能产生压力保护作用。这些数据表明，运动或健身本身并不足以产生压力恢复能力。相反，锻炼加上“感知控制”的心理变量可能是至关重要的。这是一个重要的区别，因为它意味着参与控制感知的不同神经基质（如内侧前额叶皮层；mPFC）与那些仅仅通过体育活动本身（如去甲肾上腺素能系统）参与运动产生的压力恢复能力。事实上，我们已经观察到，自愿运动可以同时激活这两种系统；反复激活可通过抑制5-HT1A基因抑制因子弗洛伊德-1的活性，促进drn5 -HT1A自身受体的增加。目前的项目测试了以下假设：1)轮式跑步通过防止DRN 5-HT1A自身受体脱敏和/或增加mPFC对DRN的抑制作用来预防LH； 2)轮式跑步对行为和5-HT1A自身受体的影响取决于运动的可控性；3)反复激活mPFC和/或drn11 - adr有助于增加5-HT1A自身受体和轮式跑步对LH的保护作用。